Individuals with chronic conditions such as heart disease and diabetes show impaired glucose and fatty acid oxidation and diminished energetic states in various tissue/organ systems. This is due to alterations in the signaling, biochemical, and structural components of metabolic pathways [63-69]. For example, remodeling in failing hearts results in impaired ability to oxidize both fatty acids and glucose [66], due to a down regulation of enzymes involved in poxidation [70, 71] along with an impaired ability to utilize glucose due to suppression of glycolytic activity and decreased ability of the cardiomyocytes to take up glucose [72]. In the extreme, the work capacity of the heart is limited not by the availability of substrates or O2, but by the impaired ability to consume the available substrates [65]. As H. Taegtmeyer has put it, "...the heart fails in the midst of plenty" [73]. The goal of this scientific project is to understand the interactions among the transport and metabolic processes comprising energy metabolism at various biological scales (transporters/enzymes, mitochondria, cells, tissues/organs, whole-organism) in healthy and complex disease states. Specifically, models will account for the transport and metabolic characteristics of 5 rat strains identified in Section 1.3. The phenotypes associated with these strains are system properties that influence and are influenced by the metabolic state. Thus the metabolic modeling component of the VPR will be crucial to simulating complex traits associated with these strains. To test the robustness of the integrated metabolic model, the model will be used to simulate and predict physiological responses (e.g., substrate utilization and switching) to acetyl-CoA carboxylase 2 knock-out (ACC2(-/-)) which will be compared to measured physiological phenotypes. Since the metabolic inputs and outputs of all organs are coupled by transport through the cardiovascular system (CVS), the whole-body energy metabolism and solute transport models must be ultimately be coupled to the CVS models of Project 1.